tbuckley/cabot-search huggingface dataset:
Building epigenetic clocks for estimating accelerating aging in patients with testicular cancer treated with cisplatin-based chemotherapy.
Authors: Marcin W Wojewodzic, K. Aurora Sydhagen, Trine B. Rounge
Journal: Journal of Clinical Oncology (2023)

e24099 Background: DNA methylation is highly correlated with chronological age. This is essential for constructing epigenetic clocks. Epigenetic clocks can shade light not only about the biological age, but also describe the functional state of the body after chemotherapy (CT). Patients with testicular cancer (TC) treated with CT are prone to develop metabolic syndrome (MetS) later in life, that may be also mediated through epigenetic changes (Bucher, Clin Epigenetics. 2019; 11:179). If age acceleration is also a mediator in the CT~MetS relationship remains unknown. We developed an epigenetic clock, and then analyzed differences in biological age acceleration between groups of TC patients 16 years after CT. TC patients had undergone one of two treatments: either surgery or a combination of CT or surgery only. Half of the patients in both treatment-groups had developed MetS. Methods: First, we used an elastic net to develop epigenetic clocks based on DNA methylation from publicly available data sets (EPIC array). We tested the differences in age accelerations (residual and intrinsic age acceleration) between groups of TC patients that received CT and orchiectomy with those TC patients with orchiectomy only. Also, the linear regression used treatment type and MetS diagnosis as independent variables. Results: Five epigenetic clocks were developed, of which one, performing best, was chosen to be used in further analyses. This clock, the Aurora’s clock, had a root mean square error of 3.1/3.8 and R2 of 0.95/0.9 shown in two different test sets. In addition to Aurora’s clock, eABEC and Levine DNAm PhenoAge were used (Lee, BMC Genomics. 2020, 21, 747; Levine, Aging. 2018, 2018,10:573-591). The linear regressions indicated a lower age acceleration for the group treated with both CT and surgery, compared to the group treated with surgery only. The significance level varied between the clocks, with a p-value ranging from 0.03 to 0.17. All three clocks estimated a higher age acceleration for patients diagnosed with MetS, but this was only significant when applying Levine DNAm PhenoAge (p = 0.03 for residual age acceleration, and p = 0.045 for intrinsic age acceleration). Conclusions: These findings indicate that CT does not lead to increased age acceleration 16 years after treatment. However, individuals diagnosed with MetS can have an elevated age acceleration. These findings can have clinical implications for managing patients' after TC diagnosis (i.e. MetS can be predicted from age acceleration). Testing the clocks in an independent cohort of TC is needed for validation of our results.
Efficacy of adjuvant therapy in patients (pts) with AJCC v8 stage IIIA cutaneous melanoma.
Authors: Piyush Grover, Isabel Li, Anke Kuijpers, Firas Y. Kreidieh, Andrew Williamson, Teresa Maria Santos Amaral, Florentia Dimitriou, Joanna Placzke, Kelly Olino, Maria Grazia Vitale, Philippe Saiag, Ralf Gutzmer, Clara Allayous, Roger Olofsson Bagge, Nethanel Asher, Tarek Meniawy, Aleigha Lawless, Lydia Warburton, Alexander M. Menzies, Georgina V. Long
Journal: Journal of Clinical Oncology (2023)

9518 Background: Pts with resected AJCC v8 stage IIIA melanoma have been under-represented in clinical trials of adjuvant drug therapy. The benefit of adjuvant targeted and immunotherapy in this population is unclear. Methods: In this multicenter, retrospective study, pts with stage IIIA melanoma (AJCC v8) who received adjuvant pembrolizumab or nivolumab (PD1), BRAF/MEK-targeted therapy dabrafenib + trametinib (TT), or no adjuvant treatment (OBS) were included. Recurrence free survival (RFS), distant metastasis free survival (DMFS), and toxicity rates were examined. Results: 613 pts from 34 centers across Australia, Europe and USA were included. The median follow-up was 2.6 yrs (IQR, 1.6-3.4 yrs). Pt characteristics and follow-up were similar across the cohorts (Table). Completion rates of 12-month PD1 and TT therapy were 57.0% and 69.2% respectively. 1-yr RFS was 93.3% (95% CI, 90.3-96.4) in PD1, 100% in TT and 91.3% (95% CI, 88.1-94.7) in OBS cohorts. 2-yr RFS was 79.3% (95% CI, 74.1-84.8) for PD1, 100% for TT and 84.3% (95% CI, 79.9-89.0) in OBS cohorts. 2-yr DMFS was 88.4% (95% CI, 84.3-92.8) in PD1, 100% in TT and 91.1% (95% CI, 87.7-94.7) in OBS cohorts. Risk of recurrence was associated with higher breslow thickness (HR 1.73, 95% CI 1.36-2.20), higher mitotic rate (HR 1.07, 95% CI 1.02-1.12) and neck as the site of nodal metastases (HR 2.71, 95% CI 1.45-5.06) in the overall cohort (p&lt;0.05). Neck nodal metastases were associated with higher risk of recurrence in OBS cohort (HR 3.82, 95% CI 1.91-7.66; p&lt;0.05) but not in the PD1 cohort. Rates of ≥ Grade 3 toxicities were 10.9% with PD1 and 20.0% with TT; discontinuation due to toxicity occurred in 25.0% and 30.0%, respectively. No new safety signals were observed. Rates of unresolved toxicity at last follow-up were 26.9% in PD1 and 7.7% in TT cohorts. Conclusions: In this large international study, adjuvant PD1 or TT did not significantly improve RFS or DMFS compared to OBS in pts with resected stage IIIA melanoma. Prognosis in stage IIIA melanoma is favourable and outcomes after adjuvant therapy in this population needs further study in prospective randomised trials. [Table: see text]
Evaluation of palbociclib in combination with topotecan and cyclophosphamide in pediatric patients with recurrent or refractory neuroblastoma.
Authors: Theodore Willis Laetsch, Fariba Navid, Brenda Weigel, Elizabeth Fox, Douglas S. Hawkins, Jodi Ann Muscal, Katarzyna Alicja Juszczak-Kosela, Zhe Zhang, Margaret E Macy
Journal: Journal of Clinical Oncology (2023)

TPS10069 Background: Palbociclib is an orally administered, highly selective, reversible, small molecule cyclin-dependent kinases 4/6 (CDK4/6) inhibitor. Inhibition of CDK4/6 reduced growth of neuroblastoma cell lines. The phase 1 portion of the study, conducted and funded by Pfizer in collaboration with the Children's Oncology Group, established the recommended phase 2 dose (RP2D) of palbociclib with topotecan and cyclophosphamide (TOPO/CTX) in children with solid tumors. Per study protocol, if 2 or more patients from the phase 1 study show a confirmed objective response (OR) in a specific tumor type, an open-label, non-randomized tumor-specific cohort (TSC) may be opened. Methods: A neuroblastoma TSC has been opened to evaluate the preliminary antitumor activity of palbociclib with TOPO/CTX in the treatment of patients with recurrent/refractory neuroblastoma using a modified Simon’s 2-stage optimal design. Up to 21 patients will be enrolled and receive palbociclib with TOPO/CTX. The primary endpoint is OR, as assessed by investigator using International Neuroblastoma Response Criteria (INRC). Secondary efficacy endpoints include duration of response, progression-free survival, and overall survival. Key eligibility criteria include: recurrent/refractory neuroblastoma, measurable disease as defined by INRC, aged ≥2 and &lt; 21 years at the time of study entry, adequate blood counts organ function, and performance status. Patients may have received prior TOPO and/or CTX, provided their disease did not progress on this regimen. Prior treatment with a CDK4/6 inhibitor is exclusionary. Patients will receive palbociclib at the RP2D of 75 mg/m 2 orally once daily on days 1–14 of each 21-day treatment cycle. CTX (250 mg/m 2 ) followed by TOPO (0.75 mg/m 2 ) will be administered intravenously once daily on days 1–5. Concurrent radiotherapy or surgery for local control will be permitted. Treatment will continue until disease progression, patient and/or legal guardian refusal, unacceptable toxicity , or up to 24 months of treatment, whichever occurs first. Enrollment in the neuroblastoma TSC was initiated in December 2022 ( NCT03709680 ). Clinical trial information: NCT03709680 .
Non-comparative, open-label, international, multicenter phase I/II study of nivolumab (NIVO) ± ipilimumab (IPI) in patients (pts) with recurrent/metastatic merkel cell carcinoma (MCC) (CheckMate 358).
Authors: Shailender Bhatia, Suzanne Louise Topalian, William Howard Sharfman, Tim Meyer, Christopher D. Lao, Lorena Fariñas-Madrid, Lot A. Devriese, Raid Aljumaily, Robert L. Ferris, Yoshitaka Honma, Tariq Aziz Khan, Anjaiah Srirangam, Charlie Garnett-Benson, Michelle Lee, Paul Nghiem
Journal: Journal of Clinical Oncology (2023)

9506 Background: MCC is a rare and aggressive skin cancer. Programmed death-ligand 1 (PD-L1) is often upregulated in MCC and blockade of PD-L1 or its receptor, PD-1, has improved survival for patients with metastatic MCC. Anti–PD-1 combined with anti–CTLA-4 has been reported to improve outcomes over anti–PD-1 monotherapy (NCT03071406; Kim S et al., Lancet 2022), however further investigation is needed. CheckMate 358 (NCT02488759) assessed NIVO ± IPI in 2 non-randomized MCC cohorts. Methods: Eligible pts had recurrent or metastatic MCC, ≤ 2 prior therapies, ECOG performance status (PS) 0–1, and no prior immune checkpoint inhibitor (ICI) therapy. Pts were eligible regardless of PD-(L)1 status. Pts received NIVO 240 mg Q2W or NIVO 3 mg/kg Q2W + IPI 1 mg/kg Q6W for ≤ 24 months (m) or until disease progression, unacceptable toxicity, or consent withdrawal. Imaging was conducted Q8W in year 1 and Q12W thereafter. Planned sample sizes were 23 pts for NIVO and 40 pts for NIVO + IPI. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included duration of response (DOR), investigator-assessed progression-free survival (PFS), and overall survival (OS). Results: 68 pts received NIVO (n = 25) or NIVO + IPI (n = 43) with ≥ 24 m follow-up (median: NIVO, 62.5 m; NIVO + IPI, 24.4 m). In the NIVO arm, median age was 66 yrs (range, 27–88), 10 (40.0%) pts had ECOG PS of 1, and 15 (60.0%) were treatment-naive. In the NIVO + IPI arm, median age was 70 yrs (range, 48–85), 27 (62.8%) pts had ECOG PS of 1, and 33 (76.7%) were treatment-naive. Treatment duration was 15.8 m in the NIVO arm, and 7.9 m for NIVO and 6.0 m for IPI in the NIVO + IPI arm. Efficacy and safety outcomes are summarized in the table. ORR was 60.0% (95% CI, 38.7–78.9) in the NIVO arm and 58.1% (95% CI, 42.1–73.0) in the NIVO + IPI arm. The most common reasons for treatment discontinuation were disease progression (NIVO, 28.0%; NIVO + IPI, 32.6%) or study-drug toxicity (NIVO, 20.0%; NIVO + IPI, 25.6%). There was 1 study drug-related death in each arm (NIVO, pneumonitis; NIVO + IPI, gastrointestinal motility disorder). Conclusions: Both NIVO and NIVO + IPI show durable clinical efficacy in advanced MCC. While the non-randomized trial design limits comparisons between the arms, results do not suggest additional efficacy benefit with IPI added to NIVO. Higher incidence of grade 3/4 TRAEs observed in the combination arm could have resulted in shorter treatment duration. Clinical trial information: NCT02488759 . [Table: see text]
Phase II clinical trial of camrelizumab combined with famitinib for advanced acral and mucosal melanoma.
Authors: Lili Mao, Lu Si, Caili Li, Xue Bai, Jie Dai, Xiaoting Wei, Yan Kong, Chuanliang Cui, Zhihong Chi, Xinan Sheng, Bin Lian, Xuan Wang, Bixia Tang, Siming Li, Xieqiao Yan, Li Zhou, Juan Li, Xiaowen Wu, Huajun Li, Jun Guo
Journal: Journal of Clinical Oncology (2023)

9550 Background: Acral and mucosal melanoma were rarely seen in Caucasians but common in Asians. Previous studies revealed that acral and mucosal melanoma are more aggressive than cutaneous melanoma with a high unmet need for effective treatments. Camrelizumab plus anti-angiogenic agents have shown promising antitumor activity in previously untreated melanoma. Famitinib, a selective multiple-target tyrosine kinase inhibitor that exhibits both anti-angiogenesis and antiproliferative effects via targeting VEGFR-2, PDGFR, c-kit, FGFR and so on, combined with camrelizumab had been proven effective in multiple cancers. This study aimed to assess the antitumor activity and safety of camrelizumab plus famitinib in both immunotherapy naïve and experienced advanced mucosal or acral melanoma. Methods: This single-center, open-label phase II study recruited patients (pts) with advanced acral and mucosal melanoma. Pts who were immune checkpoint inhibitors (ICI) treatment naïve were in cohort 1, while pts experienced ICI in cohort 2. In both cohorts, pts received camrelizumab (200 mg i.v. q3w) and famitinib (20 mg po qd) until disease progression or intolerable toxicity. The primary endpoint was objective response rate (ORR) per RECIST1.1. Secondary endpoints included progression free survival (PFS), disease control rate (DCR), overall survival (OS), and safety. This analysis focused on cohort 2. Results: As of January 12, 2023, 18 pts (9 mucosal and 9 acral histology subtypes) were enrolled in cohort 2. The median age of all pts was 58 yrs (ranged 38-71 yrs); 9 pts (50.0%) were female; prevalence of mutations: BRAF (11.1%), C-KIT or NRAS (16.7% each); 38.9% received ≥2 prior treatments. All pts progressed after anti-PD-1/L1 monotherapy (27.8%) or combinational therapy (66.7%), except one progressed after 4-1BB mAb monotherapy. The combination drugs included anti-LAG-3/CTLA-4 antibodies (38.9%), oncolytic viruses (11.1%), c-kit inhibitors, chemotherapy and anti-angiogenic agents (5.6% each). The median follow-up was 7.3 months (ranged 4.6-14.7 months). At the data cutoff, 5 pts remained on treatment. 17 pts were evaluable. The ORR and DCR were 17.6% and 64.7%, including two pts with confirmed PR, and one with unconfirmed PR, all of which were acral subtype. The median PFS was 6.0 months. The median OS was not reached. Of 18 pts, the incidence of treatment-related adverse events (TRAEs) was 88.9%. The most common grade 3 TRAEs was neutrophil count decreased (11.1%). No grade 4 TRAEs and no treatment-related deaths occurred. Conclusions: Camrelizumab plus famitinib showed promising antitumor activity in ICI-experienced advanced acral and mucosal melanoma pts, and was generally well tolerated. Clinical trial information: NCT05051865 .
Unmasking the MASCC score: A retrospective study.
Authors: Sumukh Arun Kumar, Fnu Janamejey, Sushmita Prabhu, Pramukh Arun Kumar, Chidambaram Ramasamy, George M. Abraham, Kala Seetharaman
Journal: Journal of Clinical Oncology (2023)

e18763 Background: Febrile neutropenia (FN) is a common oncological emergency in patients receiving anticancer treatments. The Multinational Association for Supportive Care in Cancer (MASCC) and the Clinical Index of the Stable Febrile Neutropenia (CISNE) are validated risk assessment tools widely used to guide the need for hospital admission. There is sparse research regarding the utility of these scores in predicting in-hospital outcomes. Methods: We conducted a retrospective chart review of patients admitted with FN from 2012 to 2022 in our community-based teaching hospital and compared the performances of MASCC and CISNE scores on in-hospital outcomes such as length of hospital stay, duration of intravenous (IV) antibiotics, intensive care unit (ICU) admission, pressor use, length of ICU stay, in-hospital mortality and cost of hospital stay. Logistic regression was applied to calculate the unadjusted odds ratio for qualitative outcomes and linear regression to calculate the association for quantitative outcomes. Results: Among 139 patients screened, 100 met the inclusion criteria. Sixty eight percent of patients were 65 years or older, 53% were females, the most common presenting complaint was fever/chills (46%) and 67% had underlying hematologic malignancies. Patients with high-risk MASCC scores (HM) were noted to have higher odds of ICU admission (OR 20.3), pressor use (OR 5.09), and in-hospital mortality (OR 4.11) compared to those with low-risk MASCC scores (LM). Patients with HM had 3.3 days longer hospital stay and 2.3 days longer ICU stay compared to patients with LM with the mean duration being 6.5 days and 1.59 days, respectively. Patients with HM required 3.1 additional days of IV antibiotics compared to those with LM, with the mean duration of 5.23 days. The mean cost of stay was 52,890 USD, with an additional cost of 42,086.95 USD for patients with HM than for patients with LM. Comparisons of CISNE scores showed no statistical significance for any of the above-mentioned hospital outcomes and cost of the stay. Conclusions: FN patients with HM were found to have worse in-hospital outcomes and more expensive hospital stay than patients with LM. Our study highlighted the utility of MASCC score as a potential screening tool at the time of admission to predict severity of illness and guide resource utilization. [Table: see text]
Racial disparities in treatment and outcomes of pediatric hepatoblastoma.
Authors: Taylor Billion, Eva Holland, Peter T. Silberstein, Marco Braaten
Journal: Journal of Clinical Oncology (2023)

10062 Background: Hepatoblastoma is the most common malignant liver tumor which affects pediatric patients. However, the incidence is rare with 100 cases reported per year. 1 Current management consists of surgery and adjuvant cisplatin chemotherapy and radiation depending on tumor histology, resectability, and metastasis. 2 However, due to its rarity, optimal treatment protocol remains unclear. The 5-year overall survival rate in the US is approximately 57-69% 1 . Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with hepatoblastoma from 2004 to 2020 using the histology codes 8970 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, Chi-Square, and ANOVA tests were performed. Data was analyzed using SPSS version 27 and statistical significance was set at α = 0.05. Results: This study identified 1215 patients with hepatoblastoma. Black patients had a significantly lower median survival rate compared to White and other race patients (126.2 months vs 165.4 months vs 166.1 months; all p&lt;0.05). Black patients were more likely to be from low-income households than White patients (29.6% vs 17.3%; p&lt;0.05). The mean age of diagnosis was higher for Black patients compared to White patients (2.42 vs 1.99; p&lt;0.05). Black patients were less likely to receive surgery (63.5% vs. 75.4%; p&lt;0.05). Black patients on average had shorter distances to travel from their residence to the hospital (30.61 vs. 59.52 miles; p&lt;0.05). Black patients had longer mean stay times compared to white patients (16.7 days vs 11.2 days; p&lt;0.05). There was no significant difference in survival across incomes. When comparing Black and White patients there was no significant difference in insurance type, surgical margins, grade, stage, size of tumor, regional lymph nodes and time of diagnosis to treatment. No significant difference was shown between adjuvant therapies including chemotherapy and radiation. Conclusions: This study showed Black patients experienced inferior overall survival when diagnosed and treated for hepatoblastoma compared to White patients. This population was less likely to receive surgery, older when diagnosed, and had longer hospital stays. Poorer outcomes suggest a disparity in hepatoblastoma treatment. References: 1. Rangaswami, Arun A. “Pediatric Hepatoblastoma Treatment &amp; Management: Medical Care, Surgical Care, Consultations.” Pediatric Hepatoblastoma Treatment &amp; Management: Medical Care, Surgical Care, Consultations, Medscape, 9 Dec. 2021, https://emedicine.medscape.com/article/986802-treatment . 2. Pritchard J, Brown J, Shafford E, et al.: Cisplatin, doxorubicin, and delayed surgery for childhood hepatoblastoma: a successful approach--results of the first prospective study of the International Society of Pediatric Oncology. J Clin Oncol 18 (22): 3819-28, 2000.
Use of antibiotics and outcomes of patients presenting to emergency department with non-neutropenic fever and/or suspected infection.
Authors: Zeba Siddiqui, Yuchen Li, Elaine Jin, Peter Michael Ellis
Journal: Journal of Clinical Oncology (2023)

e18693 Background: Current guidelines are clear about antibiotic choices for cancer patients presenting to emergency department (ED) with febrile neutropenia. However, there is little known about antibiotic use and outcomes of cancer patients who present to ED with non-neutropenic fever. The objective of this study was to identify antibiotic prescribing pattern of patients with solid tumor malignancies who presented to Juravinski Hospital (JH) emergency department (ED) with non-neutropenic fever or/and suspected infection. Methods: A retrospective cohort review was completed. All patients with solid tumor malignancies followed by an oncologist at Juravinski Cancer Centre (JCC) who presented to JH ED with non-neutropenic fever or suspected infection from July 1 to December 31, 2020 were identified from an electronic database. Patients’ baseline characteristics, antibiotics used, and outcome information were collected. The primary outcome was proportion of patients who received broad spectrum antibiotic(s) (either Piperacillin and Tazobactam, a Carbapenem, or/and Cefepime) during ED visit or hospital admission. Results: A total of 581 patients were identified and 275 met inclusion criteria. Median age was 71 years, with 46% male. Most common cancer types were breast (21%), lung (18%), gastrointestinal (16%), and genitourinary (13%). Most patients had advanced cancer [stage 4 (59%), stage 3 (14%)], and 37% were on active systemic treatment at the time of ED presentation. A source of infection was identified in 68% of patients, which included 83/187 (44%) respiratory, 32/187 (17%) cutaneous or soft tissue, 24/187 (13%) genitourinary, 20/187 (11%) gastrointestinal, 14/187 (5%) hepatobiliary, and 12/187 iatrogenic (4%). Majority of ED visits (73%) resulted in hospital admission. Median duration of hospital stay was 6 days, and death occurred in 12% of the admitted patients. Broad-spectrum intravenous antibiotics were used in 47% of patients, and most of the time (78%) was the first antibiotic type given after arrival in ED. Conclusions: In our single-centre study, nearly half of patients with solid tumor malignancies who presented to ED with non-neutropenic fever or/and suspected infection received broad spectrum intravenous antibiotics typically recommended in febrile neutropenia protocols. These data suggest a need for quality improvement strategies to improve antibiotic stewardship for patients with solid tumour malignancies presenting to ED with non-neutropenic fever.